Pharmaceutical composition

ABSTRACT

A pharmaceutical composition is described. The composition comprises: (i) a drug component comprising at least one indacaterol compound selected from indacaterol and the pharmaceutically acceptable derivatives thereof; and (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a).

The present invention relates to the delivery of drug formulations froma medical device, such as a metered dose inhaler (MDI), using apropellant comprising 1,1-difluoroethane (HFA-152a). More particularly,the present invention relates to pharmaceutical compositions comprisingHFA-152a propellant and a drug formulation which is dissolved orsuspended in the propellant and to medical devices containing thosecompositions. The pharmaceutical compositions of the invention areparticularly suited for delivery from a pressurised aerosol containerusing a metered dose inhaler (MDI).

MDIs are the most significant type of inhalation drug delivery systemand are well known to those skilled in the art. They are designed todeliver, on demand, a discrete and accurate amount of a drug to therespiratory tract of a patient using a liquefied propellant in which thedrug is dissolved, suspended or dispersed. The design and operation ofMDIs is described in many standard textbooks and in the patentliterature. They all comprise a pressurised container that holds thedrug formulation, a nozzle and a valve assembly that is capable ofdispensing a controlled quantity of the drug through the nozzle when itis activated. The nozzle and valve assembly are typically located in ahousing that is equipped with a mouth piece. The drug formulation willcomprise a propellant, in which the drug is dissolved, suspended ordispersed, and may contain other materials such as polar excipients,surfactants and preservatives.

In order for a propellant to function satisfactorily in MDIs, it needsto have a number of properties. These include an appropriate boilingpoint and vapour pressure so that it can be liquefied in a closedcontainer at room temperature but develop a high enough pressure whenthe MDI is activated to deliver the drug as an atomised formulation evenat low ambient temperatures. Further, the propellant should be of lowacute and chronic toxicity and have a high cardiac sensitisationthreshold. It should have a high degree of chemical stability in contactwith the drug, the container and the metallic and non-metalliccomponents of the MDI device, and have a low propensity to extract lowmolecular weight substances from any elastomeric materials in the MDIdevice. The propellant should also be capable of maintaining the drug ina homogeneous solution, in a stable suspension or in a stable dispersionfor a sufficient time to permit reproducible delivery of the drug inuse. When the drug is in suspension in the propellant, the density ofthe liquid propellant is desirably similar to that of the solid drug inorder to avoid rapid sinking or floating of the drug particles in theliquid. Finally, the propellant should not present a significantflammability risk to the patient in use. In particular, it should form anon-flammable or low flammability mixture when mixed with air in therespiratory tract.

Dichlorodifluoromethane (R-12) possesses a suitable combination ofproperties and was for many years the most widely used MDI propellant,often blended with trichlorofluoromethane (R-11). Due to internationalconcern that fully and partially halogenated chlorofluorocarbons (CFCs),such as dichlorodifluoromethane and trichlorofluoromethane, weredamaging the earth's protective ozone layer, many countries entered intoan agreement, the Montreal Protocol, stipulating that their manufactureand use should be severely restricted and eventually phased outcompletely. Dichlorodifluoromethane and trichlorofluoromethane werephased out for refrigeration use in the 1990's, but are still used insmall quantities in the MDI sector as a result of an essential useexemption in the Montreal Protocol.

1,1,1,2-tetrafluoroethane (HFA-134a) was introduced as a replacementrefrigerant and MDI propellant for R-12.1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) was also introduced as areplacement propellant for dichlorotetrafluoroethane (R-114) in the MDIsector and is sometimes used alone or blended with HFA-134a for thisapplication.

Although HFA-134a and HFA-227ea have low ozone depletion potentials(ODPs), they have global warming potentials (GWPs), 1430 and 3220respectively, which are now considered to be too high by some regulatorybodies, especially for dispersive uses when they are released into theatmosphere.

One industrial area that has received particular attention recently hasbeen the automotive air-conditioning sector where the use of HFA-134ahas come under regulatory control as a result of the European Mobile AirConditioning Directive (2006/40/EC). Industry is developing a number ofpossible alternatives to HFA-134a in automotive air conditioning andother applications that have a low greenhouse warming potential (GWP) aswell as a low ozone depletion potential (ODP). Many of thesealternatives include hydrofluoropropenes, especially thetetrafluoropropenes, such as 2,3,3,3-tetrafluoropropene (HFO-1234yf) and1,3,3,3-tetrafluoropropene (HFO-1234ze).

Although the proposed alternatives to HFA-134a have a low GWP, thetoxicological status of many of the components, such as certain of thefluoropropenes, is unclear and they are unlikely to be acceptable foruse in the MDI sector for many years, if at all.

Indacaterol(5-[(1R)-2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one)is a long acting beta-2 agonist (LABA) used in the treatment and controlof a number of respiratory-related disorders but particularly chronicobstructive pulmonary disease (COPD). Whilst indacaterol treatment isvery effective, the performance of indacaterol in many of thesetherapies may be improved by administration in combination with a longacting muscarinic agonist (LAMA) agent such as glycopyrronium bromide(3-[2-Cyclopentyl(hydroxy)phenylacetoxy]-1,1-dimethylpyrrolidiniumbromide) (glycopyrrolate).

Unfortunately, it has proven difficult to formulate indacaterol in aform that is suitable for delivery using a MDI due to its limitedphysical and chemical stability. As a result, commercial inhalationproducts currently utilize dry-powder delivery technology where the drugis dispersed on a pharmaceutically acceptable solid carrier anddelivered to the lung without a propellant using a dry powder deliverydevice.

There is a need for a pharmaceutical composition of indacaterol whichcan be delivered using a MDI and that uses a propellant having a reducedGWP in comparison with HFA-134a and HFA-227ea. There is also a need fora pharmaceutical composition of indacaterol which exhibits improvedstability.

We have found that the issues associated with the use ofindacaterol-based formulations in MDIs may be overcome by using apropellant that comprises 1,1-difluoroethane (HFA-152a), particularlywhere the formulations contain low amounts of water. These formulationscan exhibit improved chemical stability, improved aerosolisationperformance for improved drug delivery, good suspension stability,reduced GWP, good compatibility with standard uncoated aluminium cans aswell as good compatibility with standard valves and seals.

According to a first aspect of the present invention, there is provideda pharmaceutical composition, e.g. a pharmaceutical suspension or apharmaceutical solution, said composition comprising:

-   (i) a drug component comprising at least one indacaterol compound    selected from indacaterol and the pharmaceutically acceptable    derivatives thereof; and-   (ii) a propellant component comprising 1,1-difluoroethane    (HFA-152a).

The pharmaceutical composition of the first aspect of the inventiontypically contains less than 500 ppm of water based on the total weightof the pharmaceutical composition. The improved chemical stability isobserved, in particular, when the pharmaceutical composition containsless than 100 ppm, preferably less than 50 ppm, more preferably lessthan 10 ppm and particularly less than 5 ppm of water based on the totalweight of the pharmaceutical composition. In referring to the watercontent of the pharmaceutical composition, we are referring to thecontent of free water in the composition and not any water that happensto be present in any hydrated drug compounds that may be used as part ofthe drug component. In an especially preferred embodiment, thepharmaceutical composition is water-free. Alternatively, thepharmaceutical composition of the first aspect may contain greater than0.5 ppm of water, e.g. greater than 1 ppm, but less than the amountsdiscussed above, as it can in practice be difficult to remove all thewater from the composition and then retain it in such a water-freestate.

Accordingly a preferred embodiment of the first aspect of the presentinvention provides a pharmaceutical composition, e.g. a pharmaceuticalsuspension or a pharmaceutical solution, said composition comprising:

-   (i) a drug component comprising at least one indacaterol compound    selected from indacaterol and the pharmaceutically acceptable    derivatives thereof; and-   (ii) a propellant component comprising 1,1-difluoroethane    (HFA-152a),    -   wherein the composition contains less than 100 ppm, preferably        less than 50 ppm, more preferably less than 10 ppm and        especially less than 5 ppm of water based on the total weight of        the pharmaceutical composition.

In a preferred embodiment, the pharmaceutical composition of the firstaspect of the invention contains less than 1000 ppm, preferably lessthan 500 ppm, more preferably less than 100 ppm and particularly lessthan 50 ppm of dissolved oxygen based on the total weight of thepharmaceutical composition. In an especially preferred embodiment, thepharmaceutical composition is oxygen-free. Alternatively, thepharmaceutical composition of the first aspect may contain greater than0.5 ppm of oxygen, e.g. 1 ppm or greater, but less than the amountsdiscussed above, as it can in practice be difficult to retain thecomposition in an oxygen-free state. Low oxygen contents are preferredbecause they tend to reduce the degradation of the drug compoundsresulting in a composition with higher chemical stability.

Accordingly a preferred embodiment of the first aspect of the presentinvention provides a pharmaceutical composition, e.g. a pharmaceuticalsuspension or a pharmaceutical solution, said composition comprising:

-   (i) a drug component comprising at least one indacaterol compound    selected from indacaterol and the pharmaceutically acceptable    derivatives thereof; and-   (ii) a propellant component comprising 1,1-difluoroethane    (HFA-152a), wherein the composition contains less than 1000 ppm,    preferably less than 500 ppm, more preferably less than 100 ppm and    especially less than 50 ppm of oxygen based on the total weight of    the pharmaceutical composition.

The pharmaceutical composition of the present invention is suitable fordelivery to the respiratory tract using a metered dose inhaler (MDI).

The at least one indacaterol compound in the pharmaceutical compositionof the invention in all aspects and embodiments disclosed herein ispreferably in a micronized form. Further, the pharmaceutical compositionof the invention in all aspects and embodiments disclosed herein ispreferably free of perforated microstructures.

The at least one indacaterol compound may be dispersed or suspended inthe propellant. The drug particles in such suspensions preferably have adiameter of less than 100 microns, e.g. less than 50 microns. Inpreferred embodiments, the drug particles in the suspension have adiameter of less than 3 microns.

In an alternative embodiment the pharmaceutical compositions of theinvention are solutions with the at least one indacaterol compounddissolved in the propellant, e.g. with the assistance of a polarexcipient, such as ethanol.

Suitable pharmaceutically acceptable derivatives of indacaterol include,inter alia, pharmaceutically acceptable salts, pharmaceuticallyacceptable prodrugs, pharmaceutically acceptable solvates,pharmaceutically acceptable hydrates, pharmaceutically acceptableesters, solvates of pharmaceutically acceptable salts, solvates ofpharmaceutically acceptable prodrugs, hydrates of pharmaceuticallyacceptable salts and hydrates of pharmaceutically acceptable prodrugs. Apreferred pharmaceutically acceptable derivative of indacaterol is apharmaceutically acceptable salt thereof, especially indacaterolmaleate. In a particularly preferred embodiment, the at least oneindacaterol compound in the pharmaceutical composition of the firstaspect of the invention is indacaterol itself or indacaterol maleate.

Accordingly, in the above described pharmaceutical compositions of theinvention, the at least one indacaterol compound is preferably selectedfrom indacaterol itself or indacaterol maleate.

The amount of the drug component in the pharmaceutical composition ofthe first aspect of the present invention will typically be in the rangeof from 0.01 to 2.5 weight % based on the total weight of thepharmaceutical composition. Preferably, the drug component will comprisefrom 0.01 to 2.0 weight %, more preferably from 0.05 to 2.0 weight % andespecially from 0.05 to 1.5 weight % of the total weight of thepharmaceutical composition. The drug component may consist essentiallyof or consist entirely of the at least one indacaterol compound selectedfrom indacaterol and the pharmaceutically acceptable derivativesthereof. By the term “consists essentially of”, we mean that at least 98weight %, more preferably at least 99 weight % and especially at least99.9 weight % of the drug component consists of the least oneindacaterol compound. Alternatively, the drug component may containother drugs, such as glycopyrrolate and/or at least one corticosteroid.

The propellant component in the pharmaceutical composition of the firstaspect of the present invention comprises 1,1-difluoroethane (HFA-152a).Thus, we do not exclude the possibility that the propellant componentmay include other propellant compounds in addition to the HFA-152a. Forexample, the propellant component may additionally comprise one or moreadditional hydrofluorocarbon or hydrocarbon propellant compounds, e.g.selected from HFA-227ea, HFA-134a, difluoromethane (HFA-32), propane,butane, isobutane and dimethyl ether. The preferred additionalpropellants are HFA-227ea and HFA-134a.

If an additional propellant compound is included, such as HFA-134a orHFA-227ea, at least 5% by weight, preferably at least 10% by weight andmore preferably at least 50% by weight of the propellant componentshould be HFA-152a. Typically, the HFA-152a will constitute at least 90weight %, e.g. from 90 to 99 weight %, of the propellant component.Preferably, the HFA-152a will constitute at least 95 weight %, e.g. from95 to 99 weight %, and more preferably at least 99 weight % of thepropellant component.

In a preferred embodiment, the propellant component has a global warmingpotential (GWP) of less than 250, more preferably less than 200 andstill more preferably less than 150.

In an especially preferred embodiment, the propellant component consistsentirely of HFA-152a so that the pharmaceutical composition of theinvention comprises HFA-152a as the sole propellant. By the term“consists entirely of” we do not, of course, exclude the presence ofminor amounts, e.g. up to a few hundred parts per million, of impuritiesthat may be present following the process that is used to make theHFA-152a providing that they do not affect the suitability of thepropellant in medical applications. Preferably the HFA-152a propellantwill contain no more than 10 ppm, e.g. from 0.5 to 10 ppm, morepreferably no more than 5 ppm, e.g. from 1 to 5 ppm, of unsaturatedimpurities, such as vinyl fluoride, vinyl chloride, vinylidene fluorideand chloro-fluoro ethylene compounds.

The amount of propellant component in the pharmaceutical composition ofthe invention will vary depending on the amounts of the drugs and othercomponents in the pharmaceutical composition. Typically, the propellantcomponent will comprise from 80.0 to 99.99 weight % of the total weightof the pharmaceutical composition. Preferably, the propellant componentwill comprise from 90.0 to 99.99 weight %, more preferably from 96.5 to99.99 weight % and especially from 97.5 to 99.95 weight % of the totalweight of the pharmaceutical composition.

In one embodiment, the pharmaceutical composition of the first aspect ofthe present invention consists essentially of and more preferablyconsists entirely of the two components (i) and (ii) listed above. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the pharmaceutical composition consists of the two listedcomponents.

In another embodiment, the pharmaceutical composition of the firstaspect of the present invention additionally includes a polar excipient,such as ethanol. Polar excipients have been used previously inpharmaceutical compositions for treating respiratory disorders that aredelivered using metered dose inhalers (MDIs). They are also referred toas solvents, co-solvents, carrier solvents and adjuvants. Theirinclusion can serve to solubilise the surfactant or the drug in thepropellant and/or inhibit deposition of drug particles on the surfacesof the metered dose inhaler that are contacted by the pharmaceuticalcomposition as it passes from the container in which it is stored to thenozzle outlet. They are also used as bulking agents in two-stage fillingprocesses where the drug is mixed with a suitable polar excipient.

The most commonly used polar excipient is ethanol. If a polar excipientis used, it will typically be present in an amount of from 0.5 to 10% byweight, preferably in an amount of from 1 to 5% by weight based on thetotal weight of the pharmaceutical composition.

In one preferred embodiment, the pharmaceutical composition of thepresent invention is free of polar excipients such as ethanol.

The pharmaceutical composition of the first aspect of the presentinvention may also include a surfactant component comprising at leastone surfactant compound. Surfactant compounds of the type that have beenin use hitherto in pharmaceutical formulations for MDIs may be used inthe pharmaceutical compositions of the present invention. Preferredsurfactants are selected from polyvinylpyrrolidone, polyethylene glycolsurfactants, oleic acid and lecithin. By the term oleic acid, we are notnecessarily referring to pure (9Z)-octadec-9-enoic acid. When sold forsurfactant use in medical applications, oleic acid is typically amixture of several fatty acids, with (9Z)-octadec-9-enoic acid being thepredominant fatty acid, e.g. present in an amount of at least 65 weight% based on the total weight of the surfactant.

In a preferred embodiment, the surfactant component consists essentiallyof and still more preferably consists entirely of at least onesurfactant compound selected from polyvinylpyrrolidone, polyethyleneglycols, oleic acid and lecithin. In a particularly preferredembodiment, the surfactant component consists essentially of and stillmore preferably consists entirely of at least one surfactant compoundselected from polyvinylpyrrolidone and polyethylene glycols. By the term“consists essentially of”, we mean that at least 95 weight %, morepreferably at least 98 weight % and especially at least 99 weight % ofthe surfactant component is composed of the listed surfactants.

If a surfactant component is used, it will typically be present in anamount of from 0.1 to 2.5% by weight, preferably in an amount of from0.2 to 1.5% by weight based on the total weight of the pharmaceuticalcomposition.

In a preferred embodiment, the pharmaceutical composition of the firstaspect of the present invention is free of acid stabilisers, such asorganic and inorganic acids.

The pharmaceutical composition of the invention may also include apharmaceutically acceptable salt of glycopyrrolate (also known asglycopyrronium). Glycopyrrolate is a quaternary ammonium salt. Suitablecounter ions are pharmaceutically acceptable counter ions including, forexample, fluoride, chloride, bromide, iodide, nitrate, sulfate,phosphate, formate, acetate, trifluoroacetate, propionate, butyrate,lactate, citrate, tartrate, malate, maleate, succinate, benzoate,p-chlorobenzoate, diphenyl-acetate or triphenylacetate,o-hydroxybenzoate, p-hydroxybenzoate,1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate,methanesulfonate and benzenesulfonate. A preferred compound is thebromide salt of glycopyrrolate also known as glycopyrronium bromide.

Accordingly, a second aspect of the present invention provides apharmaceutical composition, e.g. a pharmaceutical suspension or apharmaceutical solution, said composition comprising:

-   (i) a drug component comprising at least one indacaterol compound    selected from indacaterol and the pharmaceutically acceptable    derivatives thereof, especially indacaterol and indacaterol maleate,    and at least one pharmaceutically acceptable salt of glycopyrrolate,    especially glycopyrronium bromide; and-   (ii) a propellant component comprising 1,1-difluoroethane    (HFA-152a).

The pharmaceutical composition of the second aspect of the inventiontypically contains less than 500 ppm of water based on the total weightof the pharmaceutical composition. Preferably, the pharmaceuticalcomposition of the second aspect of the present invention contains lessthan 100 ppm, more preferably less than 50 ppm, particularly less than10 ppm and especially less than 5 ppm of water based on the total weightof the pharmaceutical composition. It has been found that small amountsof water alongside the use of HFA-152a as the propellant can result in apharmaceutical composition with improved chemical stability. Inreferring to the water content of the pharmaceutical composition, we arereferring to the content of free water in the composition and not anywater that happens to be present in any hydrated drug compounds that maybe used as part of the drug component. In an especially preferredembodiment, the pharmaceutical composition of the second aspect of thepresent invention is water-free. Alternatively, the pharmaceuticalcomposition of the second aspect may contain greater than 0.5 ppm ofwater, e.g. greater than 1 ppm, but less than the amounts discussedabove, as it can in practice be difficult to remove all the water fromthe composition and then retain it in such a water-free state.

In a preferred embodiment, the pharmaceutical composition of the secondaspect of the invention contains less than 1000 ppm, preferably lessthan 500 ppm, more preferably less than 100 ppm and particularly lessthan 50 ppm of dissolved oxygen based on the total weight of thepharmaceutical composition. In an especially preferred embodiment, thepharmaceutical composition is oxygen-free.

Alternatively, the pharmaceutical composition of the second aspect maycontain greater than 0.5 ppm of oxygen, e.g. 1 ppm or greater, but lessthan the amounts discussed above, as it can in practice be difficult toretain the composition in an oxygen-free state. Low oxygen contents arepreferred because they tend to reduce the degradation of the drugcompounds resulting in a composition with higher chemical stability.

Preferred indacaterol compounds are as discussed above for thepharmaceutical composition of the first aspect of the present invention.

Typical and preferred amounts of the drug component and the propellantcomponent in the pharmaceutical composition of the second aspect of thepresent invention and suitable, typical and preferred compositions forthe propellant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. The drug component mayconsist essentially of or consist entirely of the at least oneindacaterol compound and the at least one pharmaceutically acceptablesalt of glycopyrrolate. By the term “consists essentially of”, we meanthat at least 98 weight %, more preferably at least 99 weight % andespecially at least 99.9 weight % of the drug component consists of theat least one indacaterol compound and the at least one pharmaceuticallyacceptable salt of glycopyrrolate.

In one embodiment, the pharmaceutical composition of the second aspectof the present invention consists essentially of and more preferablyconsists entirely of the two components (i) and (ii) listed above. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the pharmaceutical composition consists of the two listedcomponents.

In another embodiment, the pharmaceutical composition of the secondaspect of the invention may contain one or both of a polar excipient anda surfactant component as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. Suitable and preferredpolar excipients and surfactants are as discussed above for thepharmaceutical composition of the first aspect of the invention. Typicaland preferred amounts of the polar excipient and the surfactantcomponent are as discussed above for the pharmaceutical composition ofthe first aspect of the invention.

In an especially preferred embodiment of the second aspect of theinvention, the drug component comprises at least one indacaterolcompound selected from indacaterol and indacaterol maleate incombination with glycopyrronium bromide. Preferably, the at least oneselected indacaterol compound and the glycopyrronium bromide are theonly pharmaceutical actives in the pharmaceutical composition of thesecond aspect of the invention.

The pharmaceutical composition of the invention may also include acorticosteroid. Any of the corticosteroids that have been in usehitherto for treating asthma and chronic obstructive pulmonary diseasesand that can be delivered using a MDI can be used in the pharmaceuticalcompositions of the present invention. Suitable corticosteroids includebudesonide, mometasone, beclomethasone and fluticasone as well as theirpharmaceutically acceptable derivatives, especially theirpharmaceutically acceptable salts. Preferred compounds includebudesonide, mometasone furoate, beclomethasone dipropionate andfluticasone propionate. The most preferred corticosteroids arebudesonide, mometasone, fluticasone and beclomethasone, particularlybudesonide and mometasone and especially budesonide.

Accordingly, a third aspect of the present invention provides apharmaceutical composition, e.g. a pharmaceutical suspension or apharmaceutical solution, said composition comprising:

-   (i) a drug component comprising at least one indacaterol compound    selected from indacaterol and the pharmaceutically acceptable    derivatives thereof, especially indacaterol and indacaterol maleate,    and at least one corticosteroid, particularly at least one    corticosteroid selected from fluticasone, budesonide, mometasone and    beclomethasone and the pharmaceutically acceptable salts thereof,    especially budesonide; and-   (ii) a propellant component comprising 1,1-difluoroethane    (HFA-152a).

The pharmaceutical composition of the third aspect of the inventiontypically contains less than 500 ppm of water based on the total weightof the pharmaceutical composition. Preferably, the pharmaceuticalcomposition of the third aspect of the invention contains less than 100ppm, more preferably less than 50 ppm, particularly less than 10 ppm andespecially less than 5 ppm of water based on the total weight of thepharmaceutical composition. It has been found that small amounts ofwater alongside the use of HFA-152a as the propellant can result in apharmaceutical composition with improved chemical stability. Inreferring to the water content of the pharmaceutical composition, we arereferring to the content of free water in the composition and not anywater that happens to be present in any hydrated drug compounds that maybe used as part of the drug component. In an especially preferredembodiment, the pharmaceutical composition of the third aspect of thepresent invention is water-free. Alternatively, the pharmaceuticalcomposition of the third aspect may contain greater than 0.5 ppm ofwater, e.g. greater than 1 ppm, but less than the amounts discussedabove, as it can in practice be difficult to remove all the water fromthe composition and then retain it in such a water-free state.

In a preferred embodiment, the pharmaceutical composition of the thirdaspect of the invention contains less than 1000 ppm, preferably lessthan 500 ppm, more preferably less than 100 ppm and particularly lessthan 50 ppm of dissolved oxygen based on the total weight of thepharmaceutical composition. In an especially preferred embodiment, thepharmaceutical composition is oxygen-free. Alternatively, thepharmaceutical composition of the third aspect may contain greater than0.5 ppm of oxygen, e.g. 1 ppm or greater, but less than the amountsdiscussed above, as it can in practice be difficult to retain thecomposition in an oxygen-free state. Low oxygen contents are preferredbecause they tend to reduce the degradation of the drug compoundsresulting in a composition with higher chemical stability.

Preferred indacaterol compounds are as discussed above for thepharmaceutical composition of the first aspect of the present invention.

Typical and preferred amounts of the drug component and the propellantcomponent in the pharmaceutical composition of the third aspect of thepresent invention and suitable, typical and preferred compositions forthe propellant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. The drug component mayconsist essentially of or consist entirely of the at least oneindacaterol compound and the at least one corticosteroid. By the term“consists essentially of”, we mean that at least 98 weight %, morepreferably at least 99 weight % and especially at least 99.9 weight % ofthe drug component consists of the at least one indacaterol compound andthe at least one corticosteroid.

In one embodiment, the pharmaceutical composition of the third aspect ofthe present invention consists essentially of and more preferablyconsists entirely of the two components (i) and (ii) listed above. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the pharmaceutical composition consists of the two listedcomponents.

In another embodiment, the pharmaceutical composition of the thirdaspect of the invention may contain one or both of a polar excipient anda surfactant component as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. Suitable and preferredpolar excipients and surfactants are as discussed above for thepharmaceutical composition of the first aspect of the invention. Typicaland preferred amounts of the polar excipient and the surfactantcomponent are as discussed above for the pharmaceutical composition ofthe first aspect of the invention.

In an especially preferred embodiment of the third aspect of theinvention, the drug component comprises at least one indacaterolcompound selected from indacaterol and indacaterol maleate incombination with budesonide. Preferably, the at least one selectedindacaterol compound and budesonide are the only pharmaceutical activesin the pharmaceutical composition of the third aspect of the invention.

The pharmaceutical composition of the invention may also include aglycopyrrolate salt and a corticosteroid. Any of the glycopyrrolatesalts and corticosteroids discussed above can be used. Suitable andpreferred glycopyrrolate salts are as discussed above for the secondaspect of the invention. Suitable and preferred corticosteroids are asdiscussed above for the third aspect of the present invention.

Accordingly, a fourth aspect of the present invention provides apharmaceutical composition, e.g. a pharmaceutical suspension or apharmaceutical solution, said composition comprising:

-   (i) a drug component comprising at least one indacaterol compound    selected from indacaterol and the pharmaceutically acceptable    derivatives thereof, especially indacaterol and indacaterol maleate,    at least one pharmaceutically acceptable salt of glycopyrrolate,    especially glycopyrronium bromide and at least one corticosteroid,    particularly at least one corticosteroid selected from fluticasone,    budesonide, mometasone and beclomethasone and the pharmaceutically    acceptable salts thereof, especially budesonide; and-   (ii) a propellant component comprising 1,1-difluoroethane    (HFA-152a).

The pharmaceutical composition of the fourth aspect of the inventiontypically contains less than 500 ppm of water based on the total weightof the pharmaceutical composition. In this fourth aspect of the presentinvention, the pharmaceutical composition preferably contains less than100 ppm, more preferably less than 50 ppm, particularly less than 10 ppmand especially less than 5 ppm of water based on the total weight of thepharmaceutical composition. It has been found that small amounts ofwater alongside the use of HFA-152a as the propellant can result in apharmaceutical composition with improved chemical stability. Inreferring to the water content of the pharmaceutical composition, we arereferring to the content of free water in the composition and not anywater that happens to be present in any hydrated drug compounds that maybe used as part of the drug component. In an especially preferredembodiment, the pharmaceutical composition of the fourth aspect of thepresent invention is water-free. Alternatively, the pharmaceuticalcomposition of the fourth aspect may contain greater than 0.5 ppm ofwater, e.g. greater than 1 ppm, but less than the amounts discussedabove, as it can in practice be difficult to remove all the water fromthe composition and then retain it in such a water-free state.

In a preferred embodiment, the pharmaceutical composition of the fourthaspect of the invention contains less than 1000 ppm, preferably lessthan 500 ppm, more preferably less than 100 ppm and particularly lessthan 50 ppm of dissolved oxygen based on the total weight of thepharmaceutical composition. In an especially preferred embodiment, thepharmaceutical composition is oxygen-free. Alternatively, thepharmaceutical composition of the fourth aspect may contain greater than0.5 ppm of oxygen, e.g. 1 ppm or greater, but less than the amountsdiscussed above, as it can in practice be difficult to retain thecomposition in an oxygen-free state. Low oxygen contents are preferredbecause they tend to reduce the degradation of the drug compoundsresulting in a composition with higher chemical stability.

Preferred indacaterol compounds are as discussed above for thepharmaceutical composition of the first aspect of the present invention.

Typical and preferred amounts of the drug component and the propellantcomponent in the pharmaceutical composition of the fourth aspect of thepresent invention and suitable, typical and preferred compositions forthe propellant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. The drug component mayconsist essentially of or consist entirely of the at least oneindacaterol compound, the at least one pharmaceutically acceptable saltof glycopyrrolate and the at least one corticosteroid. By the term“consists essentially of”, we mean that at least 98 weight %, morepreferably at least 99 weight % and especially at least 99.9 weight % ofthe drug component consists of the at least one indacaterol compound,the at least one pharmaceutically acceptable salt of glycopyrrolate andthe at least one corticosteroid.

In one embodiment, the pharmaceutical composition of the fourth aspectof the present invention consists essentially of and more preferablyconsists entirely of the two components (i) and (ii) listed above. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the pharmaceutical composition consists of the two listedcomponents.

In another embodiment, the pharmaceutical composition of the fourthaspect of the invention may contain one or both of a polar excipient anda surfactant component as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. Suitable and preferredpolar excipients and surfactants are as discussed above for thepharmaceutical composition of the first aspect of the invention. Typicaland preferred amounts of the polar excipient and the surfactantcomponent are as discussed above for the pharmaceutical composition ofthe first aspect of the invention.

In an especially preferred embodiment of the fourth aspect of theinvention, the drug component comprises at least one indacaterolcompound selected from indacaterol and indacaterol maleate,glycopyrronium bromide and budesonide. Preferably, the at least oneselected indacaterol compound, the glycopyrronium bromide and thebudesonide are the only pharmaceutical actives in the pharmaceuticalcomposition of the fourth aspect of the invention.

It has been found that the use of propellants comprising1,1-difluoroethane (HFA-152a) in pharmaceutical compositions containingan indacaterol compound, such as indacaterol itself or indacaterolmaleate, and the propellant can unexpectedly improve the chemicalstability of the indacaterol compound compared to the stability itexhibits in formulations containing either HFA-134a or HFA-227ea as thepropellant.

Accordingly, in a fifth aspect of the present invention there isprovided a method of improving the stability of a pharmaceuticalcomposition comprising a propellant component and a drug componentcomprising at least one indacaterol compound selected from indacateroland the pharmaceutically acceptable derivatives thereof, said methodcomprising using a propellant component comprising 1,1-difluoroethane(HFA-152a).

The pharmaceutical composition in the stabilisation method of the fifthaspect of the present invention may be a suspension or a solution.

The improved chemical stability can result, in particular, when thepharmaceutical composition contains less than 500 ppm, preferably lessthan 100 ppm, more preferably less than 50 ppm, still more preferablyless than 10 ppm and particularly less than 5 ppm of water based on thetotal weight of the pharmaceutical composition. In referring to thewater content of the pharmaceutical composition, we are referring to thecontent of free water in the composition and not any water that happensto be present in any hydrated drug compounds that may be used as part ofthe drug component. In an especially preferred embodiment, thepharmaceutical composition is water-free. Alternatively, thepharmaceutical composition recited in the fifth aspect of the presentinvention may contain greater than 0.5 ppm of water, e.g. greater than 1ppm, but less than the amounts discussed above, as it can in practice bedifficult to remove all the water from the composition and then retainit in such a water-free state.

Accordingly, in a preferred embodiment of the fifth aspect of thepresent invention there is provided a method of improving the stabilityof a pharmaceutical composition comprising a propellant component and adrug component comprising at least one indacaterol compound selectedfrom indacaterol and the pharmaceutically acceptable derivativesthereof, said method comprising using a propellant component comprising1,1-difluoroethane (HFA-152a) and selecting the components andconditions for the preparation of the pharmaceutical composition tomaintain the water content of the pharmaceutical composition below 100ppm, preferably below 50 ppm, more preferably below 10 ppm andparticularly below 5 ppm based on the total weight of the pharmaceuticalcomposition.

In practice, preparing a pharmaceutical composition with the low waterlevels recited above involves using a propellant component with asuitably low water content, as it is usually the largest mass item inthe finished device, and then preparing the pharmaceutical compositionunder suitably dry conditions, e.g. in a dry nitrogen atmosphere.Preparing pharmaceutical compositions under dry conditions is well knownand the techniques involved are well understood by those skilled in theart. Other steps to obtain a low water content in the finished deviceinclude drying and storing the can and valve components in amoisture-controlled atmosphere, e.g. dry nitrogen or air, prior to andduring device assembly. If the pharmaceutical composition contains asignificant amount of ethanol, then it may also be important to controlthe water content of the ethanol as well as the propellant, e.g. bydrying to reduce the water content to suitably low levels. Suitabledrying techniques are well known to those skilled in the art and includethe use of a molecular sieve or other inorganic desiccant and membranedrying processes.

In the stabilisation method of the fifth aspect of the present inventionsuitable and preferred indacaterol compounds and derivatives thereof areas described above for the pharmaceutical composition of the firstaspect of the present invention. In addition, typical and preferredamounts of the drug component and the propellant component in thestabilisation method of the fifth aspect of the present invention andsuitable, typical and preferred compositions for the propellantcomponent are as discussed above for the pharmaceutical composition ofthe first aspect of the invention.

The drug component in the stabilisation method of the fifth aspect ofthe present invention may consist essentially of or consist entirely ofthe at least one indacaterol compound selected from indacaterol and thepharmaceutically acceptable derivatives thereof. By the term “consistsessentially of”, we mean that at least 98 weight %, more preferably atleast 99 weight % and especially at least 99.9 weight % of the drugcomponent consists of the least one indacaterol compound. Alternatively,the drug component may additionally comprise at least one corticosteroidand/or at least one pharmaceutically acceptable salt of glycopyrrolate(hereinafter also referred to as a glycopyrrolate salt for convenience).When a corticosteroid and/or a glycopyrrolate salt are included,suitable and preferred corticosteroids and suitable and preferredglycopyrrolate salts are as described above for the pharmaceuticalcompositions of the second and third aspects of the present invention.

In one embodiment, the pharmaceutical composition in the fifth aspect ofthe present invention consists essentially of and more preferablyconsists entirely of the drug component and the propellant component asdefined above. By the term “consists essentially of”, we mean that atleast 98 weight %, more preferably at least 99 weight % and especiallyat least 99.9 weight % of the pharmaceutical composition consists of thetwo components.

In an alternative embodiment, the pharmaceutical composition in thefifth aspect of the invention may contain one or both of a polarexcipient and a surfactant component as discussed above for thepharmaceutical composition of the first aspect of the invention.Suitable and preferred polar excipients and surfactants are as discussedabove for the pharmaceutical composition of the first aspect of theinvention. Typical and preferred amounts of the polar excipient and thesurfactant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention.

In one preferred stabilisation method, the resulting pharmaceuticalcomposition after storage at 40° C. and 75% relative humidity for 1month will produce less than 0.25% by weight, preferably less than 0.15%by weight and more preferably less than 0.1% by weight of impuritiesfrom the degradation of the at least one indacaterol compound based onthe total weight of the at least one indacaterol compound and theimpurities.

In another preferred stabilisation method in which the pharmaceuticalcomposition also comprises at least one corticosteroid and/or at leastone pharmaceutically acceptable salt of glycopyrrolate, the resultingpharmaceutical composition after storage at 40° C. and 75% relativehumidity for 1 month will produce less than 0.25% by weight, preferablyless than 0.15% by weight and more preferably less than 0.1% by weightof impurities from the degradation of the at least one indacaterolcompound based on the total weight of the at least one indacaterolcompound and the impurities.

In a further preferred stabilisation method, the resultingpharmaceutical composition after storage at 40° C. and 75% relativehumidity for 3 months will produce less than 0.3% by weight, preferablyless than 0.25% by weight and more preferably less than 0.2% by weightof impurities from the degradation of the at least one indacaterolcompound based on the total weight of the at least one indacaterolcompound and the impurities.

In another preferred stabilisation method in which the pharmaceuticalcomposition also comprises at least one corticosteroid and/or at leastone pharmaceutically acceptable salt of glycopyrrolate, the resultingpharmaceutical composition after storage at 40° C. and 75% relativehumidity for 3 months will produce less than 0.3% by weight, preferablyless than 0.25% by weight and more preferably less than 0.2% by weightof impurities from the degradation of the at least one indacaterolcompound based on the total weight of the at least one indacaterolcompound and the impurities.

In yet another preferred stabilisation method, at least 98.0% by weightand preferably at least 98.5% by weight of the at least one indacaterolcompound that is contained originally in the pharmaceutical compositionimmediately following preparation will be present in the compositionafter storage at 40° C. and 75% relative humidity for 3 months.

In still another preferred stabilisation method in which thepharmaceutical composition also comprises at least one corticosteroidand/or at least one pharmaceutically acceptable salt of glycopyrrolate,at least 98.0% by weight and preferably at least 98.5% by weight of theat least one indacaterol compound that is contained originally in thepharmaceutical composition immediately following preparation will bepresent in the composition after storage at 40° C. and 75% relativehumidity for 3 months.

In a further preferred stabilisation method, at least 98.0% and morepreferably at least 98.5% of the original pharmaceutical activity of thecomposition is retained after storage at 40° C. and 75% relativehumidity for 3 months.

One preferred pharmaceutical composition of the first, second, third andfourth aspects of the present invention will produce less than 0.25% byweight, preferably less than 0.15% by weight and more preferably lessthan 0.1% by weight of total impurities from the degradation of the atleast one indacaterol compound after storage at 40° C. and 75% relativehumidity for 1 month.

Another preferred pharmaceutical composition of the first, second, thirdand fourth aspects of the present invention will produce less than 0.3%by weight, preferably less than 0.25% by weight and more preferably lessthan 0.2% by weight of total impurities from the degradation of the atleast one indacaterol compound after storage at 40° C. and 75% relativehumidity for 3 months.

The weight % of impurities indicated above are based on the total weightof the at least one indacaterol compound and the impurities.

In a further preferred pharmaceutical composition of the first, second,third and fourth aspects of the present invention at least 98.0% byweight and preferably at least 98.5% by weight of the at least oneindacaterol compound that is contained originally in the pharmaceuticalcomposition of the invention immediately following preparation will bepresent in the composition after storage at 40° C. and 75% relativehumidity for 3 months.

In yet another preferred pharmaceutical composition of the first,second, third and fourth aspects of the present invention at least 98.0%and preferably at least 98.5% of the original pharmaceutical activity ofthe pharmaceutical composition of the invention is retained afterstorage at 40° C. and 75% relative humidity for 3 months.

In referring to the storage of the pharmaceutical compositions in theabove described stabilisation methods, we are referring, in particular,to the storage of those compositions in uncoated aluminium containers.Similarly, in referring to the storage of the above describedpharmaceutical compositions, we are referring, in particular, to theirstorage in uncoated aluminium containers.

It has been found that the use of propellants comprising1,1-difluoroethane (HFA-152a) in pharmaceutical compositions containingan indacaterol compound that is dispersed or suspended in the propellantcan unexpectedly increase the time it takes for the particulate drug tosettle following thorough dispersion in the propellant compared to thesettling times that are observed when either HFA-134a or HFA-227ea isused as the propellant.

Accordingly, in a sixth aspect of the present invention there isprovided a method of increasing the settling time of a pharmaceuticalcomposition comprising a propellant component and a drug componentcomprising at least one indacaterol compound selected from indacateroland the pharmaceutically acceptable derivatives thereof which issuspended in the propellant component, said method comprising using apropellant component comprising 1,1-difluoroethane (HFA-152a).

In one preferred embodiment of the sixth aspect of the presentinvention, the settling time is at least 1.5 minutes following completedispersion in the HFA-152a-conatining propellant, more preferably atleast 1.8 minutes.

In the method of the sixth aspect of the present invention suitable andpreferred indacaterol compounds and derivatives thereof are as describedabove for the pharmaceutical composition of the first aspect of thepresent invention. In addition, typical and preferred amounts of thedrug component and the propellant component in the method of the sixthaspect of the present invention and suitable, typical and preferredcompositions for the propellant component are as discussed above for thepharmaceutical composition of the first aspect of the invention.

The drug component in the method of the sixth aspect of the presentinvention may consist essentially of or consist entirely of the at leastone indacaterol compound selected from indacaterol and thepharmaceutically acceptable derivatives thereof. By the term “consistsessentially of”, we mean that at least 98 weight %, more preferably atleast 99 weight % and especially at least 99.9 weight % of the drugcomponent consists of the least one indacaterol compound. Alternatively,the drug component may additionally comprise at least one corticosteroidand/or at least one pharmaceutically acceptable salt of glycopyrrolate(glycopyrrolate salt). When a corticosteroid and/or a glycopyrrolatesalt are included, suitable and preferred corticosteroids and suitableand preferred glycopyrrolate salts are as described above for thepharmaceutical compositions of the second and third aspects of thepresent invention.

In one embodiment, the pharmaceutical composition in the sixth aspect ofthe present invention consists essentially of and more preferablyconsists entirely of the drug component and the propellant component asdefined above. By the term “consists essentially of”, we mean that atleast 98 weight %, more preferably at least 99 weight % and especiallyat least 99.9 weight % of the pharmaceutical composition consists of thetwo components.

In an alternative embodiment, the pharmaceutical composition in thesixth aspect of the invention may contain one or both of a polarexcipient and a surfactant component as discussed above for thepharmaceutical composition of the first aspect of the invention.Suitable and preferred polar excipients and surfactants are as discussedabove for the pharmaceutical composition of the first aspect of theinvention. Typical and preferred amounts of the polar excipient and thesurfactant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention.

It has been found that the use of a propellant comprising1,1-difluoroethane (HFA-152a) in pharmaceutical compositions containingan indacaterol compound, such as indacaterol or indacaterol maleate, andthe propellant that are designed to be delivered using a metered doseinhaler can unexpectedly improve the aerosolization performance of thepharmaceutical composition when that composition is delivered from themetered dose inhaler compared to the performance that is observed wheneither HFA-134a or HFA-227ea is used as the propellant. In particular,the fine particle fraction of the indacaterol compound in the emitteddose typically comprises at least 35 weight %, preferably at least 40weight % and more preferably at least 45 weight % of the emitted dose ofthe indacaterol compound. We are referring here, in particular, to theemitted dose that is observed immediately after the pharmaceuticalcomposition has been filled into a MDI canister and prior to any longterm storage.

Accordingly, in a seventh aspect of the present invention there isprovided a method of improving the aerosolization performance of apharmaceutical composition comprising a propellant component and a drugcomponent comprising at least one indacaterol compound selected fromindacaterol and the pharmaceutically acceptable derivatives thereof,said method comprising using a propellant component comprising1,1-difluoroethane (HFA-152a).

The pharmaceutical composition in the method of the seventh aspect ofthe present invention may be a suspension or a solution.

In a preferred embodiment of the seventh aspect of the present inventionthere is provided a method of improving the aerosolization performanceof a pharmaceutical composition comprising a propellant component and adrug component comprising at least one indacaterol compound selectedfrom indacaterol and the pharmaceutically acceptable derivativesthereof, said method comprising using a propellant component comprising1,1-difluoroethane (HFA-152a) and providing a pharmaceutical compositionwhich when delivered from a metered dose inhaler yields a fine particlefraction of the at least one indacaterol compound which is at least 35weight %, preferably at least 40 weight % and more preferably at least45 weight % of the emitted dose of the at least one indacaterolcompound.

Increasing the fine particle fraction of the emitted dose is highlybeneficial, because it is the fine drug particles that are able topenetrate into the deep bronchiole passages and the alveolar passages ofthe lung to maximise relief from the effects of an asthma attack orCOPD.

The fine particle fraction is a widely recognised term in the art. It isa measure of the mass fraction of emitted aerosol particles having adiameter below 5 μm which is generally accepted as being the mostdesirable particle size range for effective alveolar drug delivery.

In the method of the seventh aspect of the present invention suitableand preferred indacaterol compounds are as described above for thepharmaceutical composition of the first aspect of the present invention.In addition, typical and preferred amounts of the drug component and thepropellant component in the method of the seventh aspect of the presentinvention and suitable, typical and preferred compositions for thepropellant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention.

The drug component in the method of the seventh aspect of the presentinvention may consist essentially of or consist entirely of the at leastone indacaterol compound, such as indacaterol or indacaterol maleate. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the drug component consists of the least one indacaterol compound.Alternatively, the drug component may additionally comprise at least onepharmaceutically acceptable salt of glycopyrrolate and/or at least onecorticosteroid. When a glycopyrrolate salt and/or a corticosteroid areincluded, suitable and preferred glycopyrrolate salts and suitable andpreferred corticosteroids are as described above for the pharmaceuticalcompositions of the second and third aspects of the present invention.

In one embodiment, the pharmaceutical composition in the seventh aspectof the present invention consists essentially of and more preferablyconsists entirely of the drug component and the propellant component asdefined above. By the term “consists essentially of”, we mean that atleast 98 weight %, more preferably at least 99 weight % and especiallyat least 99.9 weight % of the pharmaceutical composition consists of thetwo components.

In an alternative embodiment, the pharmaceutical composition in theseventh aspect of the invention may contain one or both of a polarexcipient and a surfactant component as discussed above for thepharmaceutical composition of the first aspect of the invention.Suitable and preferred polar excipients and surfactants are as discussedabove for the pharmaceutical composition of the first aspect of theinvention. Typical and preferred amounts of the polar excipient and thesurfactant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention.

It has also been found that the use of a propellant comprising1,1-difluoroethane (HFA-152a) in pharmaceutical compositions containingan indacaterol compound, such as indacaterol or indacaterol maleate, andthe propellant that are designed to be delivered using a metered doseinhaler can unexpectedly improve the aerosolization performance of thepharmaceutical composition after storage when that composition isdelivered from the metered dose inhaler compared to the performance thatis observed when either HFA-134a or HFA-227ea is used as the propellant.In particular, the fine particle fraction of the indacaterol compound inthe emitted dose after storage of the pharmaceutical composition at 40°C. and 75% relative humidity for 3 months days is at least 30 weight %and preferably at least 35 weight % of the emitted dose of theindacaterol compound.

Accordingly, in an eighth aspect of the present invention there isprovided a method of improving the aerosolization performance afterstorage of a pharmaceutical composition comprising a propellantcomponent and a drug component comprising at least one indacaterolcompound selected from indacaterol and the pharmaceutically acceptablederivatives thereof, said method comprising using a propellant componentcomprising 1,1-difluoroethane (HFA-152a).

The pharmaceutical composition in the method of the eighth aspect of thepresent invention may be a suspension or a solution.

In a preferred embodiment of the eighth aspect of the present inventionthere is provided a method of improving the aerosolization performanceafter storage of a pharmaceutical composition comprising a propellantcomponent and a drug component comprising at least one indacaterolcompound selected from indacaterol and the pharmaceutically acceptablederivatives thereof, said method comprising using a propellant componentcomprising 1,1-difluoroethane (HFA-152a) and providing a pharmaceuticalcomposition which when delivered from a metered dose inhaler yields afine particle fraction of the at least one indacaterol compound which isat least 30 weight % and preferably at least 35 weight % of the emitteddose of the at least one indacaterol compound even after storage of thepharmaceutical composition at 40° C. and 75% relative humidity for 3months.

Increasing the fine particle fraction of the emitted dose after longterm storage is highly beneficial. As explained above, it is the finedrug particles that are able to penetrate into the deep bronchiolepassages and the alveolar passages of the lung to maximise relief fromthe effects of an asthma attack or COPD. Thus, retaining a high fineparticle fraction after storage means that the user of the MDI shouldstill receive a medically satisfactory dose of the drug even though asignificant period of time has elapsed since the pharmaceuticalcomposition was first manufactured.

In the method of the eighth aspect of the present invention suitable andpreferred indacaterol compounds are as described above for thepharmaceutical composition of the first aspect of the present invention.In addition, typical and preferred amounts of the drug component and thepropellant component in the method of the eighth aspect of the presentinvention and suitable, typical and preferred compositions for thepropellant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention.

The drug component in the method of the eighth aspect of the presentinvention may consist essentially of or consist entirely of the at leastone indacaterol compound, such as indacaterol or indacaterol maleate. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the drug component consists of the least one indacaterol compound.Alternatively, the drug component may additionally comprise at least onepharmaceutically acceptable salt of glycopyrrolate and/or at least onecorticosteroid. When a glycopyrrolate salt and/or a corticosteroid areincluded, suitable and preferred glycopyrrolate salts and suitable andpreferred corticosteroids are as described above for the pharmaceuticalcompositions of the second and third aspects of the present invention.

In one embodiment, the pharmaceutical composition in the eighth aspectof the present invention consists essentially of and more preferablyconsists entirely of the drug component and the propellant component asdefined above. By the term “consists essentially of”, we mean that atleast 98 weight %, more preferably at least 99 weight % and especiallyat least 99.9 weight % of the pharmaceutical composition consists of thetwo components.

In an alternative embodiment, the pharmaceutical composition in theeighth aspect of the invention may contain one or both of a polarexcipient and a surfactant component as discussed above for thepharmaceutical composition of the first aspect of the invention.Suitable and preferred polar excipients and surfactants are as discussedabove for the pharmaceutical composition of the first aspect of theinvention. Typical and preferred amounts of the polar excipient and thesurfactant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention.

The pharmaceutical compositions of the invention find particular utilityin the delivery of the indacaterol compounds, and where included thecorticosteroid and glycopyrrolate salt, from a pressurised aerosolcontainer, e.g. using a metered dose inhaler (MDI). For thisapplication, the pharmaceutical compositions are contained in thepressurised aerosol container and the HFA-152a propellant functions todeliver the drug as a fine aerosol spray.

The pharmaceutical compositions of the invention may comprise one ormore other additives of the type that are conventionally used in drugformulations for pressurised MDIs, such as valve lubricants. Where otheradditives are included in the pharmaceutical compositions, they arenormally used in amounts that are conventional in the art.

The pharmaceutical compositions of the invention are normally stored ina pressurised container or canister which is to be used in associationwith a medication delivery device. When so stored, the pharmaceuticalcompositions are normally a liquid. In a preferred embodiment, thepressurised container is designed for use in a metered dose inhaler(MDI). In a particularly preferred embodiment, the pressurised containeris a coated aluminium can or an uncoated aluminium can, especially thelatter.

Accordingly, a ninth aspect of the present invention provides apressurised container holding the pharmaceutical composition of thefirst, second, third or fourth aspect of the present invention. In atenth aspect, the present invention provides a medication deliverydevice, especially a metered dose inhaler, having a pressurisedcontainer holding the pharmaceutical composition of the first, second,third or fourth aspect of the present invention.

The metered dose inhaler typically comprises a nozzle and valve assemblythat is crimped to a container holding the pharmaceutical composition tobe dispensed. An elastomeric gasket is used to provide a seal betweenthe container and the nozzle/valve assembly. Preferred elastomericgasket materials are EPDM, chlorobutyl, bromobutyl and cycloolefincopolymer rubbers as these can exhibit good compatibility with HFA-152aand also provide a good barrier to prevent or limit HFA-152a permeatingfrom the container.

The pharmaceutical compositions of the present invention are for use inmedicine for treating a patient suffering or likely to suffer from arespiratory disorder and especially asthma or a chronic obstructivepulmonary disease.

Accordingly, the present invention also provides a method for treating apatient suffering or likely to suffer from a respiratory disorder,especially asthma or a chronic obstructive pulmonary disease, whichcomprises administering to the patient a therapeutically orprophylactically effective amount of a pharmaceutical composition asdiscussed above. The pharmaceutical composition is preferably deliveredto the patient using a MDI.

The pharmaceutical compositions of the invention can be prepared and theMDI devices filled using techniques that are standard in the art, suchas pressure filling and cold filling. For example, the pharmaceuticalcompositions can be prepared by a simple blending operation in which theat least one indacaterol compound, optionally the at least onecorticosteroid and/or the at least one glycopyrrolate salt, optionallythe surfactant component and the HFA-152a-containing propellant aremixed together in the required proportions in a suitable mixing vessel.Mixing can be promoted by stirring as is common in the art.Conveniently, the HFA-152a-containing propellant is liquefied to aidmixing. If the pharmaceutical composition is made in a separate mixingvessel, it can then be transferred to pressurised containers forstorage, such as pressurised containers that are used as part ofmedication delivery devices and especially MDIs.

The pharmaceutical compositions of the invention can also be preparedwithin the confines of a pressurised container, such as an aerosolcanister or vial, from which the compositions are ultimately released asan aerosol spray using a medication delivery device, such as a MDI. Inthis method, a weighed amount of the at least one indacaterol compoundand optionally the at least one corticosteroid and/or at least oneglycopyrrolate salt, is introduced into the open container. A valve isthen crimped onto the container and the HFA-152a-containing propellantcomponent, in liquid form, introduced through the valve into thecontainer under pressure, optionally after first evacuating thecontainer through the valve. The surfactant component, if included, canbe mixed with the drug(s) or, alternatively, introduced into thecontainer after the valve has been fitted, either alone or as a premixwith the propellant component. The whole mixture can then be treated todisperse the drugs in the propellant/surfactant mixture, e.g. byvigorous shaking or using an ultrasonic bath. Suitable containers may bemade of plastics, metal, e.g. aluminium, or glass. Preferred containersare made of metal, especially aluminium which may be coated or uncoated.Uncoated aluminium containers are especially preferred.

The container may be filled with enough of the pharmaceuticalcomposition to provide for a plurality of dosages. The pressurizedaerosol canisters that are used in MDIs typically contain 50 to 150individual dosages.

The present invention also provides a method of reducing the globalwarming potential (GWP) of a pharmaceutical composition comprising adrug component comprising at least one indacaterol compound selectedfrom indacaterol and the pharmaceutically acceptable derivatives thereofand a propellant component, said method comprising using a propellantcomponent comprising 1,1-difluoroethane (HFA-152a). This method isapplicable to the preparation of all the pharmaceutical compositionsdisclosed herein in all their aspects and embodiments.

Preferably, at least 90 weight %, more preferably at least 95 weight %and still more preferably at least 99 weight % of the propellantcomponent used is HFA-152a. In an especially preferred embodiment, thepropellant component used is entirely HFA-152a.

The propellant component that is used will preferably have a globalwarming potential (GWP) of less than 250, more preferably less than 200and still more preferably less than 150.

The present invention is now illustrated but not limited by thefollowing examples.

EXAMPLE 1

A number of experiments were conducted to investigate the in vitroaerosolization performance of pharmaceutical formulations of indacateroldelivered from a metered dose inhaler (MDI) using either HFA-134a orHFA-152a as the propellant after initial preparation and after storingunder stress storage conditions.

Pharmaceutical formulations of indacaterol were prepared in eitherHFA-134a or HFA-152a (Mexichem, UK). The drug was weighed directly intostandard uncoated 14 ml aluminium canisters (C128, Presspart, Blackburn,UK). The nominal dose of indacaterol was 100 μg. The canisters were thencrimped with a 50 μL valve (Bespak, Kings Lynn, UK) following which thepropellant was filled into the canisters through the valve using amanual Pamasol crimper/filler (Pamasol, Switzerland). Finally, thecanisters were sonicated for 20 minutes to aid dispersion of the drug inthe suspension.

The in vitro aerosolization performance of the formulations was testedimmediately after preparation (time t=zero) with a Next GenerationImpactor using the method described below. The formulations were thenstored under stress storage conditions (valve down) at 40° C. and 75%relative humidity for 1 month and 3 months. After storing for 1 monthand 3 months under the stress storage conditions, the in vitroaerosolization performance of the pharmaceutical formulations was testedagain as before with a Next Generation Impactor using the methoddescribed below.

The Next Generation Impactor (NGI, Copley Scientific, Nottingham UK) wasconnected to a vacuum pump (GE Motors, NJ, USA). Prior to testing, thecups of the NGI system were coated with 1% v/v silicone oil in hexane toeliminate particle bounce. For each experiment, three actuations of thevalve were discharged into the NGI at 30 L·min⁻¹ as per pharmacopeiaguidelines. Following aerosolization, the NGI apparatus was dismantledand the actuator and each part of the NGI was washed down into knownvolumes of the HPLC mobile phase. The mass of drug deposited on eachpart of the NGI was determined by HPLC. This protocol was repeated threetimes for each canister, following which, the fine particle dose (FPD)and fine particle fraction of the emitted dose (FPFED) were determined.

High performance liquid chromatography (HPLC) was used to determine drugcontent following the aerosolization studies. A 50 mm×4.6 mm Nucleosil100-3 C18 column with a 3.0 μm particle size was used for the analysis.The column was coupled to a UV detector operating at a wavelength of 220nm. The autosampler was operated at 5° C. and 100 μl samples wereinjected into the column for the analyses. The chromatographicconditions are shown in Tables 1 and 2 below.

TABLE 1 UV Pump Flow Wave- Column Rate Mobile Phase length TemperatureDrug (ml · min⁻¹) (gradient elution) (nm) (° C.) Indacaterol 1.50 MobilePhase A: 220 30 Buffer*/ Acetonitrile 75/25% v/v Mobile Phase B: Buffer/Acetonitrile 25/75% v/v *Buffer is Na₂HPO₄/triethylamine at pH 2.0

The composition of the mobile phase was varied as shown in Table 2below.

TABLE 2 Time (minutes) Volume % Mobile Phase A Volume % Mobile Phase B0.0 100 0 3.0 85 15 3.1 0 100 4.0 0 100 4.1 100 0 5.0 100 0

The results are shown in Table 3 below.

TABLE 3 In vitro aerosolization performance of indacaterol deliveredfrom a MDI using either HFA-134a or HFA-152a as the propellant at time t= 0, after storage (valve down) for 1 month at 40° C. and 75% relativehumidity and after storage (valve down) for 3 months at 40° C. and 75%relative humidity as characterised by the emitted dose, fine particledose, fine particle fraction of the emitted dose (FPF_(ED) %), massmedian aerodynamic diameter (MMAD) and geometric standard deviation(GSD). 134a 134a 152a 152a T = 1 M@ T = 3 M@ T = 1 M@ T = 3 M@ 134a 40°C./75% 40° C./75% 152a 40° C./75% 40° C./75% T = 0 RH RH T = 0 RH RHEmitted Dose (μg ± S.D.) 75.8 ± 1.8 72.3 ± 0.5 69.1 ± 0.2 74.0 ± 3.874.9 ± 0.5 71.8 ± 0.9 Fine particle Dose (μg ± S.D.) 23.8 ± 0.1 21.6 ±0.3 17.7 ± 0.5 34.6 ± 0.7 30.0 ± 1.5 27.9 ± 1.1 FPF_(ED) % ± S.D. 31.5 ±1.8 29.9 ± 0.3 25.7 ± 0.5 46.7 ± 2.8 40.0 ± 1.5 38.8 ± 1.1 MMAD (μm) 4.84.7 5.3 4.6 4.6 4.6 GSD 1.9 1.9 1.8 2.0 2.1 2.1

It can be seen from the data in Table 3 above that the fine particledose and the fine particle fraction of the emitted dose was considerablyhigher when HFA-152a was used as the propellant to deliver theindacaterol as compared to HFA-134a. In addition, when HFA-134a was usedas the propellant the aerosolization performance decreased much moredramatically after the pharmaceutical formulation had been stored understress storage conditions for 1 month and 3 months at 40° C. and 75%relative humidity than was the case when HFA-152 was used. Inparticular, the fine particle dose and fine particle fraction of theemitted dose decreased far more dramatically.

EXAMPLE 2

The chemical stability of indacaterol in HFA-134a and HFA-152a wasinvestigated at time zero (T=0) and after storage, valve down, for 1month (T=1M) and 3 months (T=3M) at 40° C. and 75% relative humidity(RH) and at 25° C. and 60% relative humidity (RH) in uncoated aluminiumcans.

The drug formulations were prepared as described in Example 1 above andanalysed using the HPLC technique described in Example 1 above.

The results of investigating the chemical stability of the indacateroldrug formulations in HFA-152a and HFA-134a in uncoated aluminium cansare shown, respectively, in Tables 4 and 5 below.

TABLE 4 Chemical stability of indacaterol in HFA-134a in uncoatedaluminium cans based on percentage assay and total impurities uponstorage at T = 0, T = 1 M @ 40° C./75% RH and 25° C./60% RH and T = 3 M@40° C./75% RH and 25° C./60% RH. Time % Assay (LC) % total impuritiesInitial time T = 0 100.5 <LoQ T = 1 M @ 25/60 99.9 <LoQ T = 1 M @40/7598.6 0.35 T = 3 M @ 25/60 98.2 0.39 T = 3 M @40/75 97.9 0.42

TABLE 5 Chemical stability of indacaterol in HFA-152a in uncoatedaluminium cans based on percentage assay and total impurities uponstorage at T = 0, T = 1 M @ 40° C./75% RH and 25° C./60% RH and T = 3 M@40° C./75% RH and 25° C./60% RH. Time % Assay (LC) % total impuritiesInitial time T = 0 99.9 <LoQ T = 1 M @ 25/60 100.5 <LoQ T = 1 M @40/7599.1 0.08 T = 3 M @ 25/60 98.8 0.14 T = 3 M @40/75 98.5 0.19

It can be seen from the data in Tables 4 and 5 above that pharmaceuticalformulations of indacaterol exhibit superior chemical stability whenblended together with HFA-152a as the aerosolization propellant.

EXAMPLE 3

Formulations containing indacaterol and either HFA-134a or HFA-152a wereprepared in PET vials and the suspension stability of the formulationsdetermined using a Turbiscan MA 2000. The Turbiscan instrument has areading head that moves along a flat-bottomed, 5 mL cylindrical glasscell, and takes readings of transmitted and backscattered light every 40μm on a maximum sample height of 80 mm. The reading head uses a pulsednear infrared light source and two synchronous detectors. Thetransmission detector picks up light transmitted through the suspensiontube at 0° and back scattering detector receives light back by theproduct at 135°.

The sedimentation and size of flocs for the different formulations areshown in Table 6 below.

TABLE 6 Suspension stability profiles of indacaterol formulations inHFA-134a and HFA-152a. Time to Size Start sediment Formulation (microns)(mins) Indacaterol and HFA-134a 3.39 1.06 Indacaterol and HFA-152a 2.511.89

It can be seen from the data in Table 6 above that pharmaceuticalformulations of indacaterol exhibit markedly superior settlingperformance when blended together with HFA-152a as the aerosolizationpropellant.

1. A pharmaceutical composition comprising: (i) a drug componentcomprising at least one indacaterol compound selected from indacateroland the pharmaceutically acceptable derivatives thereof; and (ii) apropellant component comprising 1,1-difluoroethane (HFA-152a).
 2. Thepharmaceutical composition of claim 1, wherein the composition containsless than 500 ppm, preferably less than 100 ppm, more preferably lessthan 50 ppm, still more preferably less than 10 ppm and especially lessthan 5 ppm of water based on the total weight of the pharmaceuticalcomposition.
 3. The pharmaceutical composition of claim 2, wherein thecomposition contains greater than 0.5 ppm, e.g. greater than 1 ppm, ofwater based on the total weight of the pharmaceutical composition. 4.The pharmaceutical composition of any one of the preceding claims,wherein the composition contains less than 1000 ppm, preferably lessthan 500 ppm, more preferably less than 100 ppm and particularly lessthan 50 ppm of oxygen based on the total weight of the pharmaceuticalcomposition.
 5. The pharmaceutical composition of claim 4, wherein thecomposition contains greater than 0.5 ppm, e.g. greater than 1 ppm, ofoxygen based on the total weight of the pharmaceutical composition. 6.The pharmaceutical composition of any one of the preceding claims,wherein the at least one indacaterol compound is selected fromindacaterol and indacaterol maleate.
 7. The pharmaceutical compositionof any one of the preceding claims, wherein the at least one indacaterolcompound is in a micronized form.
 8. The pharmaceutical composition ofany one of the preceding claims, wherein the drug component additionallycomprises at least one pharmaceutically acceptable salt ofglycopyrrolate.
 9. The pharmaceutical composition of claim 8, whereinthe at least one pharmaceutically acceptable salt of glycopyrrolate isglycopyrronium bromide.
 10. The pharmaceutical composition of claim 8 or9, wherein the at least one pharmaceutically acceptable salt ofglycopyrrolate is in a micronized form.
 11. The pharmaceuticalcomposition of any one of the preceding claims, wherein the drugcomponent additionally comprises at least one corticosteroid.
 12. Thepharmaceutical composition of claim 11, wherein the at least onecorticosteroid is selected from budesonide, mometasone, beclomethasone,fluticasone and the pharmaceutically acceptable salts thereof,preferably from mometasone, beclomethasone, fluticasone and thepharmaceutically acceptable salts thereof.
 13. The pharmaceuticalcomposition of claim 12, wherein the at least one corticosteroid isselected from budesonide, mometasone, mometasone furoate,beclomethasone, beclomethasone dipropionate, fluticasone and fluticasonepropionate, preferably from mometasone, mometasone furoate,beclomethasone, beclomethasone dipropionate, fluticasone and fluticasonepropionate.
 14. The pharmaceutical composition of any one of claims 11to 13, wherein the at least one corticosteroid is in a micronized form.15. The pharmaceutical composition of any one of the preceding claims,wherein the drug component comprises from 0.01 to 2.5 weight %,preferably from 0.01 to 2.0 weight %, more preferably from 0.05 to 2.0weight % and especially from 0.05 to 1.5 weight % of the total weight ofthe pharmaceutical composition.
 16. The pharmaceutical composition ofany one of the preceding claims, wherein the propellant componentcomprises from 80.0 to 99.99 weight %, preferably from 90.0 to 99.99weight %, more preferably from 96.5 to 99.99 weight % and especiallyfrom 97.5 to 99.95 weight % of the total weight of the pharmaceuticalcomposition.
 17. The pharmaceutical composition of any one of thepreceding claims, wherein at least 90 weight %, preferably at least 95weight % and more preferably at least 99 weight % of the propellantcomponent is 1,1-difluoroethane (HFA-152a).
 18. The pharmaceuticalcomposition of any one of claims 1 to 16, wherein the propellantcomponent is entirely 1,1-difluoroethane (HFA-152a).
 19. Thepharmaceutical composition of claim 17 or 18, wherein the propellantcomponent contains from 0.5 to 10 ppm, e.g. from 1 to 5 ppm, ofunsaturated impurities.
 20. The pharmaceutical composition of any one ofthe preceding claims, wherein at least 95 weight %, preferably at least98 weight % and more preferably at least 99 weight % of the compositionconsists of the two components (i) and (ii).
 21. The pharmaceuticalcomposition of any one of the preceding claims further comprising asurfactant component comprising at least one surfactant compound. 22.The pharmaceutical composition of claim 21, wherein the surfactantcomponent comprises at least one surfactant compound selected frompolyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid andlecithin.
 23. The pharmaceutical composition of any one of the precedingclaims further comprising a polar excipient.
 24. The pharmaceuticalcomposition of claim 23, wherein the polar excipient is ethanol.
 25. Thepharmaceutical composition of any one of claims 1 to 22 which is free ofpolar excipients.
 26. The pharmaceutical composition of any one ofclaims 1 to 22 which is free of ethanol.
 27. The pharmaceuticalcomposition of any one of claims 1 to 19 which consists entirely of thetwo components (i) and (ii).
 28. The pharmaceutical composition of anyone of the preceding claims which after storage in uncoated aluminiumcontainers at 40° C. and 75% relative humidity for 1 month will produceless than 0.25% by weight, preferably less than 0.15% by weight and morepreferably less than 0.1% by weight of impurities from the degradationof the at least one indacaterol compound based on the total weight ofthe at least one indacaterol compound and the impurities.
 29. Thepharmaceutical composition of any one of the preceding claims whichafter storage in uncoated aluminium containers at 40° C. and 75%relative humidity for 3 months will produce less than 0.3% by weight,preferably less than 0.25% by weight and more preferably less than 0.2%by weight of impurities from the degradation of the at least oneindacaterol compound based on the total weight of the at least oneindacaterol compound and the impurities.
 30. The pharmaceuticalcomposition of any one of the preceding claims, wherein at least 98.0%by weight and preferably at least 98.5% by weight of the at least oneindacaterol compound that is contained originally in the pharmaceuticalcomposition immediately following preparation will be present in thecomposition after storage in uncoated aluminium containers at 40° C. and75% relative humidity for 3 months.
 31. The pharmaceutical compositionof any one of claims 1 to 29, wherein at least 98.0% and preferably atleast 98.5% of the original pharmaceutical activity of the compositionis retained after storage in uncoated aluminium containers at 40° C. and75% relative humidity for 3 months.
 32. The pharmaceutical compositionof any one of the preceding claims in the form of a suspension.
 33. Thepharmaceutical composition of claim 32, wherein the drug particles inthe suspension take at least 1.5 minutes, preferably at least 1.8minutes to settle following complete dispersion of the drug particles inthe suspension.
 34. The pharmaceutical composition of any one of claims1 to 31 in the form of a solution.
 35. The pharmaceutical composition ofany one of the preceding claims, wherein the pharmaceutical compositionis free of perforated microstructures.
 36. A sealed container thatcontains a pharmaceutical composition as claimed in any one of claims 1to
 35. 37. The sealed container of claim 36 which is an uncoatedaluminium can.
 38. The sealed container of claim 36 or claim 37 which isa pressurized aerosol container for use with a metered dose inhaler(MDI).
 39. A metered dose inhaler (MDI) fitted with a sealed containeras claimed in claim
 38. 40. A method for treating a patient suffering orlikely to suffer from a respiratory disorder which comprisesadministering to the patient a therapeutically or prophylacticallyeffective amount of a pharmaceutical composition as claimed in any oneof claims 1 to
 35. 41. The method of claim 40, wherein the respiratorydisorder is asthma or a chronic obstructive pulmonary disease.
 42. Themethod of claim 40 or 41, wherein the pharmaceutical composition isdelivered to the patient using a metered dose inhaler (MDI).
 43. Amethod of improving the stability of a pharmaceutical compositioncomprising a propellant component and a drug component comprising atleast one indacaterol compound selected from indacaterol and thepharmaceutically acceptable derivatives thereof, said method comprisingusing a propellant component comprising 1,1-difluoroethane (HFA-152a).44. The method of claim 43, further comprising selecting the componentsand conditions for the preparation of the pharmaceutical composition tomaintain the water content of the pharmaceutical composition below 500ppm, preferably below 100 ppm, more preferably below 50 ppm, still morepreferably below 10 ppm and particularly below 5 ppm based on the totalweight of the pharmaceutical composition.
 45. The method of claim 43 or44, wherein the oxygen content of the resulting pharmaceuticalcomposition is below 1000 ppm, preferably below 500 ppm, more preferablybelow 100 ppm and particularly below 50 ppm based on the total weight ofthe pharmaceutical composition.
 46. The method of any one of claims 43to 45, wherein the at least one indacaterol compound is selected fromindacaterol and indacaterol maleate.
 47. The method of any one of claims43 to 46, wherein the at least one indacaterol compound is in amicronized form.
 48. The method of any one of claims 43 to 47, whereinthe drug component additionally comprises at least one pharmaceuticallyacceptable salt of glycopyrrolate.
 49. The pharmaceutical composition ofclaim 48, wherein the at least one pharmaceutically acceptable salt ofglycopyrrolate is glycopyrronium bromide.
 50. The method of claim 48 or49, wherein the at least one pharmaceutically acceptable salt ofglycopyrrolate is in a micronized form.
 51. The method of any one ofclaims 43 to 50, wherein the drug component additionally comprises atleast one corticosteroid.
 52. The method of claim 51, wherein the atleast one corticosteroid is selected from budesonide, mometasone,beclomethasone, fluticasone and the pharmaceutically acceptable saltsthereof, preferably from mometasone, beclomethasone, fluticasone and thepharmaceutically acceptable salts thereof.
 53. The method of claim 52,wherein the at least one corticosteroid is selected from budesonide,mometasone, mometasone furoate, beclomethasone, beclomethasonedipropionate, fluticasone and fluticasone propionate, preferably frommometasone, mometasone furoate, beclomethasone, beclomethasonedipropionate, fluticasone and fluticasone propionate.
 54. The method ofany one of claims 51 to 53, wherein the at least one corticosteroid isin a micronized form.
 55. The method of any one of claims 43 to 54,wherein the drug component comprises from 0.01 to 2.5 weight %,preferably from 0.01 to 2.0 weight %, more preferably from 0.05 to 2.0weight % and especially from 0.05 to 1.5 weight % of the total weight ofthe pharmaceutical composition.
 56. The method of any one of claims 43to 55, wherein the propellant component comprises from 80.0 to 99.99weight %, preferably from 90.0 to 99.99 weight %, more preferably from96.5 to 99.99 weight % and especially from 97.5 to 99.95 weight % of thetotal weight of the pharmaceutical composition.
 57. The method of anyone of claims 43 to 56, wherein at least 90 weight %, preferably atleast 95 weight % and more preferably at least 99 weight % of thepropellant component is 1,1-difluoroethane (HFA-152a).
 58. The method ofany one of claims 43 to 56, wherein the propellant component is entirely1,1-difluoroethane (HFA-152a).
 59. The method of claim 57 or 58, whereinthe propellant component contains from 0.5 to 10 ppm, e.g. from 1 to 5ppm, of unsaturated impurities.
 60. The method of any one of claims 43to 59, wherein at least 95 weight %, preferably at least 98 weight % andmore preferably at least 99 weight % of the pharmaceutical compositionconsists of the drug component and the propellant component.
 61. Themethod of any one of claims 43 to 60, wherein the pharmaceuticalcomposition further comprises a surfactant component comprising at leastone surfactant compound.
 62. The method of claim 61, wherein thesurfactant component comprises at least one surfactant compound selectedfrom polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acidand lecithin.
 63. The method of any one of claims 43 to 62 furthercomprising a polar excipient.
 64. The method of claim 63, wherein thepolar excipient is ethanol.
 65. The method of any one of claims 43 to62, wherein the pharmaceutical composition is free of polar excipients.66. The method of any one of claims 43 to 62, wherein the pharmaceuticalcomposition is free of ethanol.
 67. The method of any one of claims 43to 59, wherein the pharmaceutical composition consists entirely of thedrug component and the propellant component.
 68. The method of any oneof claims 43 to 67, wherein the pharmaceutical composition after storagein uncoated aluminium containers at 40° C. and 75% relative humidity for1 month will produce less than 0.25% by weight, preferably less than0.15% by weight and more preferably less than 0.1% by weight ofimpurities from the degradation of the at least one indacaterol compoundbased on the total weight of the at least one indacaterol compound andthe impurities.
 69. The method of any one of claims 43 to 68, whereinthe pharmaceutical composition after storage in uncoated aluminiumcontainers at 40° C. and 75% relative humidity for 3 months will produceless than 0.3% by weight, preferably less than 0.25% by weight and morepreferably less than 0.2% by weight of impurities from the degradationof the at least one indacaterol compound based on the total weight ofthe at least one indacaterol compound and the impurities.
 70. The methodof any one of claims 43 to 69, wherein at least 98.0% by weight andpreferably at least 98.5% by weight of the at least one indacaterolcompound that is contained originally in the pharmaceutical compositionimmediately following preparation will be present in the compositionafter storage in uncoated aluminium containers at 40° C. and 75%relative humidity for 3 months.
 71. The method of any one of claims 43to 69, wherein at least 98.0% and preferably at least 98.5% of theoriginal pharmaceutical activity of the composition is retained afterstorage in uncoated aluminium containers at 40° C. and 75% relativehumidity for 3 months.
 72. The method of any one of claims 43 to 71,wherein the pharmaceutical composition is in the form of a suspension.73. The method of any one of claims 43 to 71, wherein the pharmaceuticalcomposition is in the form of a solution.
 74. The method of any one ofclaims 43 to 73, wherein the pharmaceutical composition is free ofperforated microstructures.
 75. A method of increasing the settling timeof a pharmaceutical composition comprising a propellant component and adrug component comprising at least one indacaterol compound selectedfrom indacaterol and the pharmaceutically acceptable derivatives thereofwhich is suspended in the propellant component, said method comprisingusing a propellant component comprising 1,1-difluoroethane (HFA-152a).76. A method of improving the aerosolization performance of apharmaceutical composition comprising a propellant component and a drugcomponent comprising at least one indacaterol compound selected fromindacaterol and the pharmaceutically acceptable derivatives thereof,said method comprising using a propellant component comprising1,1-difluoroethane (HFA-152a).
 77. The method of claim 76, wherein themethod provides a pharmaceutical composition which when delivered from ametered dose inhaler yields a fine particle fraction which is at least35 weight %, preferably at least 40 weight % and more preferably atleast 45 weight % of the emitted dose.
 78. A method of improving theaerosolization performance after storage of a pharmaceutical compositioncomprising a propellant component and a drug component comprising atleast one indacaterol compound selected from indacaterol and thepharmaceutically acceptable derivatives thereof, said method comprisingusing a propellant component comprising 1,1-difluoroethane (HFA-152a).79. The method of claim 78, wherein the method provides a pharmaceuticalcomposition which when delivered from a metered dose inhaler yields afine particle fraction of the at least one indacaterol compound which isat least 30 weight % and preferably at least 35 weight % of the emitteddose of the at least one indacaterol compound even after storage of thepharmaceutical composition at 40° C. and 75% relative humidity for 3months.
 80. The method of any one of claims 75 to 79, wherein thepharmaceutical composition is a composition as claimed in any one ofclaims 1 to
 35. 81. The pharmaceutical composition of any one of claims1 to 35 which when delivered from a metered dose inhaler yields a fineparticle fraction of the at least one indacaterol compound which is atleast 35 weight %, preferably at least 40 weight % and more preferablyat least 45 weight % of the emitted dose of the at least one indacaterolcompound.
 82. The pharmaceutical composition of any one of claims 1 to35 and 81 which when delivered from a metered dose inhaler yields a fineparticle fraction of the at least one indacaterol compound which is atleast 30 weight % and preferably at least 35 weight % of the emitteddose of the at least one indacaterol compound even after storage of thepharmaceutical composition at 40° C. and 75% relative humidity for 3months.
 83. The metered dose inhaler of claim 39 which comprises anozzle and valve assembly attached to the pressurized aerosol containerand a gasket made from an elastomeric material selected from EPDM,chlorobutyl, bromobutyl and cycloolefin copolymer rubbers to provide aseal between the container and the nozzle/valve assembly.
 84. Themetered dose inhaler of claim 39, wherein the propellant component has aglobal warming potential (GWP) of less than 250, preferably less than200 and more preferably less than
 150. 85. The sealed container asclaimed in any one of claims 36 to 38, wherein the propellant componenthas a global warming potential (GWP) of less than 250, preferably lessthan 200 and more preferably less than
 150. 86. The pharmaceuticalcomposition of any one of claims 1 to 35, 81 and 82, wherein thepropellant component has a global warming potential (GWP) of less than250, preferably less than 200 and more preferably less than
 150. 87. Thepharmaceutical composition of any one of claims 8 to 14 which is adaptedto deliver the compounds making up the drug component in approximatelythe same proportions that they occur in the pharmaceutical composition.88. The pharmaceutical composition of any one of claims 1 to 26, 28 to35 and 81 to 83 which is free of acid stabilisers.
 89. A method ofreducing the global warming potential (GWP) of a pharmaceuticalcomposition comprising a drug component comprising at least oneindacaterol compound selected from indacaterol and the pharmaceuticallyacceptable derivatives thereof and a propellant component, said methodcomprising using a propellant component comprising 1,1-difluoroethane(HFA-152a).
 90. The method of claim 89, wherein at least 90 weight %,preferably at least 95 weight % and more preferably at least 99 weight %of the propellant component used is 1,1-difluoroethane (HFA-152a). 91.The method of claim 89, wherein the propellant component used isentirely 1,1-difluoroethane (HFA-152a).
 92. The method of claim 89,wherein the pharmaceutical composition is as claimed in any one ofclaims 1 to
 35. 93. The method of any one of claims 43 to 80 and 89 to92, wherein the propellant component used has a global warming potential(GWP) of less than 250, preferably less than 200 and more preferablyless than 150.